- RNAI-based gene therapy of hepatocellular carcinoma: targeting ABC transporters
S.J.H. van Deventer
- Award date
- 22 June 2012
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
Hepatocellular carcinoma (HCC) is a primary cancer of the liver, and HCC patients have an average survival of only 5% at 5-year post-diagnosis. This low survival has several identified causes, among which multidrug resistance i.e. resistance to chemotherapeutic treatment. These issues need be addressed in order to improve HCC management in the future. In this thesis we questioned the role of ABC transporters in HCC, and aimed at developing RNAi-based strategies to compensate their dysregulation. Two strategies were developed to modulate ABC transporter gene expression. The first one exploited endogenous regulation of ABC transporter genes by cellular miRNAs while the second strategy made use of shRNAs and artificial miRNAs for ABCC1 and ABCC2 knock-down. In conclusion, this research contributed to the development of two RNAi-based strategies to compensate ABC transporter gene dysregulation in HCC. At this moment the RNAi field faces toxicity-related and unanticipated off-targeting challenges that need to be overcome in order to take the technology forward, but once these limitations are fully apprehended, it will undoubtedly lead to significant advances for HCC diagnostics and therapeutics.
- Research conducted at: Universiteit van Amsterdam
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